Method for producing 2-alkyl-3-aminothiophene derivative

ABSTRACT

A method for reducing a sulfur-containing compound by hydrogenation using a noble metal catalyst which method is exemplified by an industrial method for producing a 2-alkyl-3-aminothiophene derivative with high economical efficiency by hydrogenating a 2-alkenyl-3-aminothiophene derivative using the noble metal catalyst. 2-Alkyl-3-aminothiophene derivatives are useful compounds in the fields of medicine and agriculture, and in particular, useful in bactericides for agriculture or gardening, or intermediates of the bactericides. The hydrogenation reaction temperature is controlled at 150° C. to 300° C. and the method allows the used noble metal catalyst to be recovered and reused.

TECHNICAL FIELD

The present invention relates to a method for reducing asulfur-containing compound by hydrogenation using a noble metalcatalyst. The present invention also relates to a method for producing a2-alkyl-3-aminothiophene derivative, which is useful in bactericides foragriculture or gardening, or an intermediate of the bactericides.

BACKGROUND ART

According to Japanese Examined Patent Application Publication No.8-32702, sulfur, and in particular, a thiophene, generally inactivatesall hydrogenation catalysts to a significant degree.

In particular, according to a paper written by Mozingo [Journal of theAmerican Chemical Society (J. Am. Chem. Soc.) Vol. 67, p. 2092 (1945)],a thiophene can be converted to a thiolane with a yield of 70%. However,this reaction requires 200% of a palladium catalyst to be added to thesubstrate. The use of this method on an industrial scale is economicallydisadvantageous.

Furthermore, it is known that a thiophene itself becomes a catalystpoison in catalytic hydrogenation of the thiophene [“Shokubai KagakuGairon” (Outline of Catalytic Chemistry) written by Tadao Shiba and twoothers, New edition, p. 121, 1956].

For the above reasons, in the reduction of a thiophene derivative byhydrogenation, a reaction example using a catalyst, which is a noblemetal such as palladium without further treatment or a palladiumcatalyst carried on a support such as activated carbon, has rarely beendescribed.

Japanese Unexamined Patent Application Publication No. 2000-327678discloses the hydrogenation of a 2-alkenyl-3-aminothiophene derivativeusing a 5%-palladium carbon. The 2-alkenyl-3-aminothiophene derivativeis represented by general formula (1):

(wherein R represents a hydrogen atom, a substituted or unsubstitutedalkyl group, a substituted or unsubstituted alkoxy group, a substitutedor unsubstituted aromatic hydrocarbon ring, a substituted orunsubstituted nonaromatic hydrocarbon ring, a substituted orunsubstituted aromatic heterocycle, or a substituted or unsubstitutednonaromatic heterocycle; R1, R2, R3, and R4 independently represent ahydrogen atom, or a linear or branched alkyl group of 1 to 12 carbonatoms; and R1 and R2, R3 and R4, R1 and R3, R1 and R4, R2 and R3, or R2and R4 may be bonded together to form a cycloalkyl group). In the abovehydrogenation, the content of the catalyst relative to the compound isabout 10%. The recovery and the reuse of the catalyst are not describedin the document. However, such a reaction, wherein no less than 10% ofthe catalyst is used in every reaction, cannot be performed economicallyon an industrial scale.

DISCLOSURE OF INVENTION

It is an object of the present invention to provide an economicallyadvantageous method for producing a sulfur-containing compound such as a2-alkyl-3-aminothiophene derivative, which is useful in bactericides foragriculture or gardening, or an intermediate of the bactericides on anindustrial scale. In the present invention, a noble metal catalyst isused to reduce a sulfur-containing compound such as a2-alkenyl-3-thiophene derivative by hydrogenation; furthermore, the usednoble metal catalyst is recovered and then reused.

In order to solve the above problems, as a result of intensive study,the present inventors have found the following facts and accomplishedthe present invention: It is fundamentally difficult to reduce thiophenederivatives by hydrogenation. Contrary to expectations, the reactioncarried out at a relatively high reaction temperature prevents theinactivation of the used noble metal catalyst. As a result, the usednoble metal catalyst can be recovered and reused.

In the present invention, a sulfur-containing compound is subjected tocatalytic hydrogenation using a noble metal catalyst, and the used noblemetal catalyst is then recovered. The recovered catalyst can be reusedfor the same reaction. The present invention includes the following twoitems: A sulfur-containing compound is subjected to catalytichydrogenation using a noble metal catalyst, and the noble metal catalystis then recovered for reuse in the same hydrogenation. In addition, whena sulfur-containing compound is subjected to catalytic hydrogenationusing a noble metal catalyst, the noble metal catalyst recovered fromthe above catalytic hydrogenation can be used as a part or all of thenoble metal catalyst in a future reaction.

The present invention includes the following Items:

-   [1] A method for reducing a sulfur-containing compound by    hydrogenation, the method including the steps of hydrogenating the    sulfur-containing compound using a noble metal catalyst at a    reaction temperature of 150° C. to 300° C., recovering the used    noble metal catalyst, and reusing the noble metal catalyst.-   [2] The method for producing a 2-alkyl-3-aminothiophene derivative    according to Item [1], wherein the noble metal catalyst is composed    of palladium.-   [3] The method for producing a 2-alkyl-3-aminothiophene derivative    according to Item [1], wherein an alcohol of 1 to 8 carbon atoms is    used as a reaction solvent in the step of hydrogenating the    sulfur-containing compound.-   [4] The method according to any one of Items [1] to [3], wherein the    sulfur-containing compound is a thiophene compound.-   [5] The method according to Item [4], wherein the thiophene compound    is a thiophene amide.-   [6] The method according to claim 5, wherein the thiophene amide is    represented by general formula (1):-    (wherein R represents a hydrogen atom, a substituted or    unsubstituted alkyl group, a substituted or unsubstituted alkoxy    group, a substituted or unsubstituted aromatic hydrocarbon ring, a    substituted or unsubstituted nonaromatic hydrocarbon ring, a    substituted or unsubstituted aromatic heterocycle, or a substituted    or unsubstituted nonaromatic heterocycle; R1, R2, R3, and R4    independently represent a hydrogen atom, or a linear or branched    alkyl group of 1 to 12 carbon atoms; and R1 and R2, R3 and R4, R1    and R3, R1 and R4, R2 and R3, or R2 and R4 may be bonded together to    form a cycloalkyl group), and an alkenyl group of the compound    represented by general formula (1) is reduced by hydrogenation to    produce a 2-alkyl-3-aminothiophene derivative represented by general    formula (2):-    (wherein R, R1, R2, R3, and R4 are as defined above).-   [7] The method according to Item [6], wherein R in the compounds    represented by general formula (1) and general formula (2) is a    hydrogen atom, a substituted or unsubstituted alkyl group, a    substituted or unsubstituted alkoxy group, or a substituted or    unsubstituted phenyl group.-   [8] The method according to Item [6], wherein R in the compounds    represented by general formula (1) and general formula (2) is a    group represented by general formulae (A1) to (A12):-    (wherein R5 represents a trifluoromethyl group, a difluoromethyl    group, a methyl group, an ethyl group, a hydrogen atom, or a halogen    atom; R6 represents a hydrogen atom, a methyl group, a    trifluoromethyl group, a halogen atom, a methoxy group, or an amino    group; R7 represents a hydrogen atom, a halogen atom, a methyl    group, or a methoxy group; R8 represents a hydrogen atom, a methyl    group, an ethyl group, or a halogen atom; and n represents an    integer of 0 to 2; however, in general formulae (A9), (A10), and    (A11), R5 does not represent a halogen atom).-   [9] The method according to Item [8], wherein R in the compounds    represented by general formula (1) and general formula (2) is    represented by general formula (A1) in which R5 is a trifluoromethyl    group and R7 is a hydrogen atom.-   [10] The method according to Item [6], wherein each of R1, R2, and    R3 in the compound represented by general formula (2) is a hydrogen    atom and R4 in the compound represented by general formula (2) is an    isopropyl group.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will now be described in detail.

In the present invention, a sulfur-containing compound represents asubstance having both a sulfur atom and an alkenyl chain in themolecule, and examples of the sulfur-containing compound according tothe present invention include a thiophene compound. In the presentinvention, the thiophene compound represents a substance having both athiophene ring and an alkenyl chain in the molecule, preferably, acompound having a carbon double bond conjugated with the thiophene ring,the double bond portion being reduced by hydrogenation. Examples of thethiophene compound include a thiophene amide. In the present invention,the thiophene amide represents a compound produced by a condensationreaction of a 2-alkenyl-3-aminothiophene and a carboxylic acid compound.Typical examples of the thiophene amide include a compound representedby general formula (1).

In the present invention, R in general formulae (1) and (2) may be ahydrogen atom. In the substituted or unsubstituted alkyl grouprepresented by R, examples of the alkyl group include methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, hexyl, decyl,methoxymethyl, ethoxymethyl, and phenylmethyl groups.

In the substituted or unsubstituted alkoxy group represented by R,examples of the alkoxy group include methoxy, ethoxy, propoxy,isopropoxy, cyclopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,cyclohexyloxy, hexyloxy, and benzyloxy groups.

Examples of the substituted or unsubstituted aromatic hydrocarbon ringrepresented by R include phenyl and substituted phenyl groups. Examplesof the substituent of the substituted phenyl group include alkyl groupssuch as methyl, ethyl, propyl, and isopropyl groups; alkoxy groups suchas methoxy, ethoxy, propoxy, and isopropoxy groups; halogen atoms suchas chlorine, bromine, fluorine, and iodine atoms; a nitro group; a cyanogroup; and an amino group.

In the substituted or unsubstituted nonaromatic hydrocarbon ringrepresented by R, examples of the nonaromatic hydrocarbon ring includecyclopropyl, cyclopentyl, cyclohexyl, and cyclohexenyl groups. Examplesof the substituent of the substituted nonaromatic hydrocarbon ringinclude the same substituents as those of the above substituted phenylgroup.

Examples of the substituted or unsubstituted aromatic heterocyclerepresented by R include pyrazolyl, thiazolyl, isothiazolyl, furyl,thienyl, pyridyl, pyrazinyl, oxazolyl, pyrrolyl, substituted pyrazolyl,substituted thiazolyl, substituted isothiazolyl, substituted furyl,substituted thienyl, substituted pyridyl, substituted pyrazinyl,substituted oxazolyl, and substituted pyrrolyl groups. Examples of thesubstituent of the substituted pyrazolyl, substituted thiazolyl,substituted isothiazolyl, substituted furyl, substituted thienyl,substituted pyridyl, substituted pyrazinyl, substituted oxazolyl, andsubstituted pyrrolyl groups include alkyl groups such as methyl, ethyl,propyl, and isopropyl groups; haloalkyl groups such as trifluoromethyland difluoromethyl groups; halogen atoms such as fluorine, chlorine,bromine, and iodine atoms; an amino group; and a cyano group.

Examples of the substituted or unsubstituted nonaromatic heterocyclerepresented by R include dihydropyranyl, dihydrofuryl, tetrahydrofuryl,2,3-dihydro-1,4-oxathiin-5-yl, substituted dihydropyranyl, substituteddihydrofuryl, substituted tetrahydrofuryl, and substituted2,3-dihydro-1,4-oxathiin-5-yl groups. Examples of the substituent of thesubstituted dihydropyranyl, substituted dihydrofuryl, substitutedtetrahydrofuryl, and substituted 2,3-dihydro-1,4-oxathiin-5-yl groupsinclude alkyl groups such as methyl, ethyl, propyl, and isopropylgroups; haloalkyl groups such as trifluoromethyl and difluoromethylgroups; halogen atoms such as fluorine, chlorine, and iodine atoms; anamino group; and a cyano group.

When R is represented by general formula (A1), the general formula (A1)represents a 4-pyrazolyl group in which R5 at the third positionrepresents a trifluoromethyl group, a difluoromethyl group, a methylgroup, an ethyl group, or a halogen atom; R7 at the fifth positionrepresents a hydrogen atom, a halogen atom, a methyl group, or a methoxygroup; and the first position is replaced with a methyl group. Examplesof such a 4-pyrazolyl group include a 1,3-dimethyl-4-pyrazolyl group,5-chloro-1,3-dimethyl-4-pyrazolyl group,5-chloro-1-methyl-3-trifluoromethyl-4-pyrazolyl group,1-methyl-3-trifluoromethyl-4-pyrazolyl group,1-methyl-3-difluoromethyl-4-pyrazolyl group,1-methyl-3-ethyl-4-pyrazolyl group, 1-methyl-3-chloro-4-pyrazolyl group,and 1-methyl-3-trifluoromethyl-5-methoxy-4-pyrazolyl group.

When R is represented by general formula (A2), the general formula (A2)represents a 5-thiazolyl group in which R5 at the fourth positionrepresents a trifluoromethyl group, a difluoromethyl group, a methylgroup,. an ethyl group, or a halogen atom; and R6 at the second positionrepresents a hydrogen atom, a methyl group, a trifluoromethyl group, ahalogen atom, a methoxy group, or an amino group. Examples of such a5-thiazolyl group include a 2-methyl-4-trifluoromethyl-5-thiazolylgroup, 2-methyl-4-difluoromethyl-5-thiazolyl group,4-trifluoromethyl-5-thiazolyl group, 2,4-dimethyl-5-thiazolyl group,2-methyl-4-ethyl-5-thiazolyl group, 2-amino-4-methyl-5-thiazolyl group,2-methoxy-4-methyl-5-thiazolyl group, and 2-chloro-4-methyl-5-thiazolylgroup.

When R is represented by general formula (A3), the general formula (A3)represents a 3-furyl group in which R5 at the second position representsa trifluoromethyl group, a difluoromethyl group, a methyl group, anethyl group, or a halogen atom; and R8 at the fifth position representsa hydrogen atom, a methyl group, an ethyl group, or a halogen atom.Examples of such a 3-furyl group include a 2-methyl-3-furyl group,2,5-dimethyl-3-furyl group, 2-chloro-3-furyl group, and2-trifluoromethyl-3-furyl group.

When R is represented by general formula (A4), the general formula (A4)represents a 2-thienyl group in which R5 at the third positionrepresents a trifluoromethyl group, a difluoromethyl group, a methylgroup, an ethyl group, or a halogen atom; and R8 at the fifth positionrepresents a hydrogen atom, a methyl group, or a halogen atom. Examplesof such a 2-thienyl group include a 3-methyl-2-thienyl group,3,5-dimethyl-2-thienyl group, 3-chloro-2-thienyl group, and3-iodo-2-thienyl group.

When R is represented by general formula (A5), the general formula (A5)represents a phenyl group in which R5 at the second position representsa trifluoromethyl group, a difluoromethyl group, a methyl group, anethyl group, or a halogen atom. Examples of such a phenyl group includea 2-trifluoromethylphenyl group, 2-difluoromethylphenyl group,2-methylphenyl group, 2-ethylphenyl group, 2-fluorophenyl group,2-chlorophenyl group, 2-bromophenyl group, and 2-iodophenyl group.

When R is represented by general formula (A6), the general formula (A6)represents a 3-pyridyl group in which R5 at the second positionrepresents a trifluoromethyl group, a difluoromethyl group, a methylgroup, an ethyl group, or a halogen atom. Examples of such a 3-pyridylgroup include a 2-trifluoromethyl-3-pyridyl group,2-difluoromethyl-3-pyridyl group, 2-methyl-3-pyridyl group,2-ethyl-3-pyridyl group, 2-fluoro-3-pyridyl group, 2-chloro-3-pyridylgroup, 2-bromo-3-pyridyl group, and 2-iodo-3-pyridyl group.

When R is represented by general formula (A7), examples of thefunctional group represented by general formula (A7) includes a2-chloro-3-pyrazinyl group. When R is represented by general formula(A8), the general formula (A8) represents a 4-thienyl group in which R5at the third position represents a trifluoromethyl group, adifluoromethyl group, a methyl group, an ethyl group, or a halogen atom.Examples of such a 4-thieny group include a 3-trifluoromethyl-4-thienygroup, 3-difluoromethyl-4-thieny group, 3-methyl-4-thieny group,3-ethyl-4-thieny group, 3-fluoro-4-thieny group, 3-chloro-4-thienygroup, 3-bromo-4-thieny group, and 3-iodo-4-thieny group.

When R is represented by general formula (A9), the general formula (A9)represents a 3,4-dihydro-2H-pyran-5-yl group in which R5 at the sixthposition represents a trifluoromethyl group, a difluoromethyl group, amethyl group, or an ethyl group. Examples of such a3,4-dihydro-2H-pyran-5-yl group include a6-trifluoromethyl-3,4-dihydro-2H-pyran-5-yl group,6-difluoromethyl-3,4-dihydro-2H-pyran-5-yl group,6-methyl-3,4-dihydro-2H-pyran-5-yl group, and2-ethyl-3,4-dihydro-2H-pyran-5-yl group.

When R is represented by general formula (A10), the general formula(A10) represents a 2,3-dihydro-1,4-oxathiin-5-yl group, a2,3-dihydro-1,4-oxathiin-4-oxido-5-yl group, or a2,3-dihydro-1,4-oxathiin-4,4-dioxido-5-yl group in which R5 at the sixthposition represents a trifluoromethyl group, a difluoromethyl group, amethyl group, or an ethyl group. Examples of such a functional groupinclude a 6-methyl-2,3-dihydro-1,4-oxathiin-5-yl group,6-methyl-2,3-dihydro-1,4-oxathiin-4-oxido-5-yl group, and6-methyl-2,3-dihydro-1,4-oxathiin-4,4-dioxido-5-yl group.

When R is represented by general formula (A11), the general formula(A11) represents a 2,3-dihydro-4-furyl group in which R5 at the fifthposition represents a trifluoromethyl group, a difluoromethyl group, amethyl group, or an ethyl group. Examples of such a 2,3-dihydro-4-furylgroup include a 5-trifluoromethyl-2,3-dihydro-4-furyl group,5-difluoromethyl-2,3-dihydro-4-furyl group, 5-methyl-2,3-dihydro-4-furylgroup, and 5-ethyl-2,3-dihydro-4-furyl group.

When R is represented by general formula (A12), the general formula(A12) represents a 4-isothiazolyl group in which R5 at the thirdposition represents a trifluoromethyl group, a difluoromethyl group, amethyl group, an ethyl group, or a halogen atom. Examples of such a4-isothiazolyl group include a 3-trifluoromethyl-4-isothiazolyl group,3-difluoromethyl-4-isothiazolyl group, 3-methyl-4-isothiazolyl group,3-ethyl-4-isothiazolyl group, 3-fluoro-4-isothiazolyl group,3-chloro-4-isothiazolyl group, 3-bromo-4-isothiazolyl group, and3-iodo-4-isothiazolyl group.

Each of R1, R2, R3, and R4 may be a hydrogen atom. Examples of an alkylgroup represented by R1, R2, R3, or R4 include linear or branched alkylgroups of 1 to 12 carbon atoms such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, hexyl, decyl, and dodecylgroups.

According to the hydrogenation in the present invention, a2-alkyl-3-aminothiophene derivative represented by general formula (2)is produced by reducing a compound represented by general formula (1):

(wherein R, R1, R2, R3, and R4 are as defined above).

The compound represented by general formula (1) is composed of fourisomers represented by general formulae (1a) to (1d):

(wherein R, R1, R2, R3, and R4 are as defined above) and exists as amixture of these 2-alkenyl-3-aminothiophene derivatives.

The reaction in the present invention can be performed by a generallyknown method such as a method under a slight pressure or a high-pressurehydrogenation using an autoclave (for example, described in Shin JikkenKagaku Kouza (New Experimental Chemistry Course), Vol. 15, Oxidation andReduction [II], Maruzen Co., Ltd, (1977)).

The catalyst used in the present invention includes a noble metalcatalyst generally used for catalytic reduction. Examples of thecatalyst include platinum group metals such as palladium, platinum,rhodium, ruthenium, and osmium. Although such a catalyst can be used ina metal state, the catalyst is generally used as a supported catalyst inwhich the metal is carried on the surface of a support such as carbon(activated carbon), barium sulfate, silica gel, alumina, and Celite. Thecontent (carried %) of the noble metal in the catalyst used in thehydrogenation is generally 1% to 20%. Although the amount of catalystused is not particularly limited, the content of the carried metal isgenerally 0.05 to 2.5 weight percent, preferably 0.025 to 0.5 weightpercent of the mixture composed of the compound represented by generalformula (1).

The catalyst used in the method of the present invention may be a newcatalyst, a recovered catalyst used in the previous reaction, or amixture thereof.

Examples of the solvent used according to need in the present inventioninclude alcohols of 1 to 8 carbon atoms such as methanol, ethanol, andoctanol; aliphatic hydrocarbons such as hexane and petroleum ether;aromatic hydrocarbons such as benzene, toluene, and anisole; ethers suchas dioxane, tetrahydrofuran, and diethyl ether; esters such as ethylacetate; aliphatic carboxylic acids such as acetic acid and propionicacid; and aprotic polar solvents such as dimethylformamide anddimethylsulfoxide. These solvents may be used in combination.

The amount of solvent used in the present invention is generally 0.1 to200 mL, preferably, 2 to 20 mL relative to 1 g of the mixture composedof the compound represented by general formula (1).

The reaction temperature of the present invention is particularlyimportant. Regarding the reaction substrate used in the presentinvention, when the reaction substrate has a sulfur atom and otherportions that are hydrogenated, the reaction is generally performed at100° C. or less in a known art in order to suppress the side reaction.Because of the poisoning of the sulfur, the catalyst cannot generally berecovered to reuse. Thus, there is no known art in which the catalyst isrecovered for reuse. However, when the reaction is performed at 150° C.to 300° C., which is the temperature condition of the present invention,by-products due to the side reaction are not generated. Furthermore,even when the recovered catalyst is reused repeatedly, the reaction canbe completed. The reaction temperature in the present invention isgenerally 150° C. to 300° C., preferably, 160° C. to 220° C. Thistemperature is applied to both a reaction performed using a new catalyst(the catalyst recovered in this reaction is reused) and a reactionpreformed reusing the recovered catalyst.

The hydrogen pressure in the present invention may be normal pressure orpressurized. When the reaction is performed in a pressurized atmosphere,the pressure is 0.098 to 30 MPa, preferably, 0.098 to 3.0 MPa.

The reaction time in the present invention is generally 0.5 to 100hours, preferably, 1 to 20 hours.

Various conditions for the catalytic hydrogenation, for example, thekind and the amount of catalyst used, the kind and the amount of solventused, the reaction temperature, the reaction pressure, and the reactiontime can be adequately selected from the numeric values in the normalrange and those in the preferable range described for each condition,and can be combined with each other.

The compound represented by general formula (2) generated afterhydrogenation, i.e., a 2-alkyl-3-aminothiophene derivative, can beprepared by filtering to remove the catalyst from the reaction mixture.The resultant mixture can be used for a subsequent process such ashydrolysis without further treatment. Alternatively, after the catalystis removed, the resultant mixture may be concentrated. Subsequently, thecompound can be isolated by crystallization.

The amount of noble metal catalyst reused is generally 10 to 100 weightpercent, preferably, 30 to 100 weight percent, more preferably, 50 to100 weight percent, still more preferably, 80 to 100 weight percent, andmost preferably, 100 weight percent of the recovered weight.

In the present invention, the recovering of the catalyst is performed asfollows: After the reaction, the catalyst is separated from the reactionsolution by, for example, filtration. During filtration, the catalystmay be washed with a solvent according to need. In general, the catalystmay be recovered at about room temperature. For example, when theviscosity of the reaction mixture is too high at room temperature, thefiltration and the washing may be performed at room temperature or ahigher temperature according to need.

Although Examples are shown to describe the present invention morespecifically, the present invention is not limited to the Examples.

The conditions for high performance liquid chromatography (HPLC) used todetermine the reaction yield described in the present Examples are asfollows: An aqueous solution of acetonitrile (50 volume percent) wasused as the mobile phase. The flow rate of the mobile phase wascontrolled to 1.0 mL/min. with an LC-10 pump (available from ShimadzuCorporation). An L-Column ODS (4.6 mm in diameter×250 mm, available fromChemicals Evaluation and Research Institute, Japan) was used as theseparation column. The detection was performed with a SPD-10A detector(available from Shimadzu Corporation) with a detection wavelength of 254nm. The compounds were quantitatively determined under the aboveconditions.

EXAMPLE 1

N-[2-(1,3-dimethylbutenyl)thiophen-3-yl] benzoic acid amide (10 g, 35.0mmol) and octanol (90 g) were charged in a 300-mL autoclave.Furthermore, 0.5 g dry weight (5% of the compound) of palladium-carbon(E106 NN/W available from Degussa) was charged in the autoclave and theautoclave was then sealed. Deaeration and purging were repeated fivetimes under a nitrogen pressure of 0.2 MPa, and the pressure in theautoclave was then returned to normal pressure. The autoclave waspressurized to 0.8 MPa with hydrogen, and was then heated to 200° C.while stirring to perform hydrogenation. Two hours later, the heatingwas stopped. The autoclave was cooled to 30° C. or less and was thendeaerated. Nitrogen purging was performed five times under a pressurizedatmosphere. The autoclave was opened and the reaction mixture wasfiltered to separate the catalyst. Furthermore, the catalyst was washedwith methanol. After the catalyst was removed, the resultant reactionmixture was analyzed by HPLC. N-[2-(1,3-dimethylbutyl)thiophen-3-yl]benzoic acid amide represented by general formula (1A5), wherein thedouble bond at the alkenyl portion of the starting material ishydrogenated, was produced with a yield of 97.4 molar percent(selectivity 98.9%).

EXAMPLE 2

The reaction was repeated as in Example 1. However, in this reaction, acatalyst including 80% of the recovered catalyst (0.67 g, i.e., 0.4 gdry weight of the catalyst), which was prepared by filtering in Example1, and 0.1 g dry weight of the new catalyst (1% of the compound) wasused. The atmosphere in the autoclave was purged with nitrogen.Subsequently, the autoclave was pressurized to 0.8 MPa with hydrogen,and was heated to 200° C. while stirring to perform hydrogenation for 8hours. The subsequent process was performed as in Example 1 to determinethe yield. The compound represented by general formula (1A5) wasproduced with a yield of 95.5 molar percent (selectivity 96.3%).

EXAMPLE 3

The reaction was repeated as in Example 2. In this reaction, a catalystincluding 80% of the recovered catalyst (0.56 g, i.e., 0.4 g dry weightof the catalyst), which was prepared by filtering in Example 2, and 0.1g dry weight of the new catalyst (1% of the compound) was used. Theatmosphere in the autoclave was purged with nitrogen. Subsequently, theautoclave was pressurized to 0.8 MPa with hydrogen, and was heated to200° C. while stirring to perform hydrogenation for 8 hours. Thesubsequent process was performed as in Example 1 to determine the yield.The compound represented by general formula (1A5) was produced with ayield of 94.5 molar percent (selectivity 95.1%).

EXAMPLE 4

The reaction was repeated as in Example 3. However, in this reaction,all the recovered catalyst (0.60 g, i.e., 0.5 g dry weight of thecatalyst), which was prepared by filtering in Example 3, was used and nonew catalyst was added. The atmosphere in the autoclave was purged withnitrogen. Subsequently, the autoclave was pressurized to 0.8·MPa withhydrogen, and was heated to 200° C. while stirring to performhydrogenation for 8 hours. The subsequent process was performed as inExample 1 to determine the yield. The compound represented by generalformula (1A5) was produced with a yield of 93.6 molar percent(selectivity 94.8%).

EXAMPLE 5

The reaction was repeated as in Example 3. In this reaction, a catalystincluding 80% of the recovered catalyst (0.56 g, i.e., 0.4 g dry weightof the catalyst), which was prepared by filtering in Example 4, and 0.1g dry weight of the new catalyst (1% of the compound) was used. Theatmosphere in the autoclave was purged with nitrogen. Subsequently, theautoclave was pressurized to 0.8 MPa with hydrogen, and was heated to200° C. while stirring to perform hydrogenation for 8 hours. Thesubsequent process was performed as in Example 1 to determine the yield.The compound represented by general formula (1A5) was produced with ayield of 94.3. molar percent (selectivity 94.6%).

EXAMPLE 6

N-[2-(1,3-dimethylbutenyl)thiophen-3-yl]-3-trifluoromethyl-1-methylpyrazole-4-carboxylicacid amide (10 g, 28.0 mmol) and octanol (90 g) were charged in a 300-mLautoclave. Furthermore, 0.5 g dry weight (5% of the compound) ofpalladium-carbon (E106 NN/W available from Degussa) was charged in theautoclave and the autoclave was then sealed. Deaeration and purging wererepeated five times under a nitrogen pressure of 0.2 MPa, and thepressure in the autoclave was then returned to normal pressure. Theautoclave was pressurized to 0.8 MPa with hydrogen, and was then heatedto 200° C. while stirring to perform hydrogenation for 2 hours. Thesubsequent process was performed as in Example 1 to determine the yield.N-[2-(1,3-dimethylbutyl)thiophen-3-yl]-3-trifluoromethyl-1-methylpyrazole-4-carboxylicacid amide represented by general formula (1A1) was produced with ayield of 98.1 molar percent (selectivity 98.6%).

EXAMPLE 7

The reaction was repeated as in Example 6. However, in this reaction, acatalyst including 80% of the recovered catalyst (0.63 g, i.e., 0.4 gdry weight of the catalyst), which was prepared by filtering in Example6, and 0.1 g dry weight of the new catalyst (1% of the compound) wasused. The atmosphere in the autoclave was purged with nitrogen.Subsequently, the autoclave was pressurized to 0.8 MPa with hydrogen,and was heated to 200° C. while stirring to perform hydrogenation for 8hours. The subsequent process was performed as in Example 1 to determinethe yield. The compound represented by general formula (1A1) wasproduced with a yield of 96.6 molar percent (selectivity 97.8%).

EXAMPLE 8

The reaction was repeated as in Example 7. In this reaction, a catalystincluding 80% of the recovered catalyst (0.56 g, i.e., 0.4 g dry weightof the catalyst), which was prepared by filtering in Example 7, and 0.1g dry weight of the new catalyst (1% of the compound) was used. Theatmosphere in the autoclave was purged with nitrogen. Subsequently, theautoclave was pressurized to 0.8 MPa with hydrogen, and was heated to200° C. while stirring to perform hydrogenation for 8 hours. Thesubsequent process was performed as in Example 1 to determine the yield.The compound represented by general formula (1A1) was produced with ayield of 95.2 molar percent (selectivity 96.0%).

EXAMPLE 9

The reaction was performed as in Example 1. In this reaction, 0.5 g dryweight (5% of the compound) of palladium-carbon (E106 NN/W availablefrom Degussa) was used as the catalyst, and octanol was used as thesolvent. The reaction was performed at 180° C. for 6 hours. Thesubsequent process was performed as in Example 1 to determine the yield.The compound represented by general formula (1A5) was produced with ayield of 97.3 molar percent (selectivity 99.1%). Subsequently, thereaction was performed at 180° C. for 10 hours using all the catalystrecovered from the above reaction system, and the yield was determined.The compound represented by general formula (1A5) was produced with ayield of 88.7 molar percent (selectivity 98.8%). Furthermore, thereaction in the second catalyst recycle was performed at 180° C. for 8hours using all the catalyst recovered from the above reaction system,and the yield was determined. The compound represented by generalformula (1A5) was produced with a yield of 84.8 molar percent(selectivity 99.0%). Although the reaction using the recovered catalystwas stopped after 8 hours, the reaction itself still proceeded.Therefore, if the reaction time had been extended, the yield could havebeen increased.

EXAMPLE 10

N-[2-(1,3-dimethylbutenyl)thiophen-3-yl] benzoic acid amide (10 g, 35.0mmol) and 2-propanol (90 g) were charged in a 300-mL autoclave.Furthermore, 0.5 g dry weight (5% of the compound) of palladium-carbon(E106 NN/W available from Degussa) was charged in the autoclave and theautoclave was then sealed. Deaeration and purging were repeated fivetimes under a nitrogen pressure of 0.2 MPa, and the pressure in theautoclave was then returned to normal pressure. The autoclave waspressurized to 3 MPa with hydrogen, and was then heated to 200° C. whilestirring to perform hydrogenation. Six hours later, the heating wasstopped. The autoclave was cooled to 30° C. or less and was thendeaerated. Nitrogen purging was performed five times at under apressurized atmosphere. The autoclave was opened and the reactionmixture was filtered to separate the catalyst. Furthermore, the catalystwas washed with methanol. After the catalyst was removed, the resultantreaction mixture was analyzed by HPLC.N-[2-(1,3-dimethylbutyl)thiophen-3-yl] benzoic acid amide represented bygeneral formula (1A5), wherein the double bond at the alkenyl portion ofthe starting material is hydrogenated, was produced with a yield of 94.3molar percent (selectivity 95.0%).

EXAMPLE 11

The reaction was repeated as in Example 10. However, in this reaction, acatalyst including 80% of the recovered catalyst (0.67 g, i.e., 0.4 gdry weight of the catalyst), which was prepared by filtering in Example10, and 0.1 g dry weight of the new catalyst (1% of the compound) wasused. The atmosphere in the autoclave was purged with nitrogen.Subsequently, the autoclave was pressurized to 3 MPa with hydrogen, andwas heated to 200° C. while stirring to perform hydrogenation for 6hours. The subsequent process was performed as in Example 1 to determinethe yield. The compound represented by general formula (1A5) wasproduced with a yield of 92.5 molar percent (selectivity 94.1%).

EXAMPLE 12

The reaction was repeated as in Example 10. In this reaction, a catalystincluding 80% of the recovered catalyst (0.66 g, i.e., 0.4 g dry weightof the catalyst), which was prepared by filtering in Example 11, and 0.1g dry weight of the new catalyst (1% of the compound) was used. Theatmosphere in the autoclave was purged with nitrogen. Subsequently, theautoclave was pressurized to 3 MPa with hydrogen, and was heated to 200°C. while stirring to perform hydrogenation for 6 hours. The subsequentprocess was performed as in Example 1 to determine the yield. Thecompound represented by general formula (1A5) was produced with a yieldof 91.8 molar percent (selectivity 94.1%).

EXAMPLE 13

N-[2-(1,3-dimethylbutenyl)thiophen-3-yl] benzoic acid amide (10 g, 35.0mmol) and 1-butanol (90 g) were charged in a 300-mL autoclave.Furthermore, 0.5 g dry weight (5% of the compound) of palladium-carbon(E106 NN/W available from Degussa) was charged in the autoclave and theautoclave was then sealed. Deaeration and purging were repeated fivetimes under a nitrogen pressure of 0.2 MPa, and the pressure in theautoclave was then returned to normal pressure. The autoclave waspressurized to 3 MPa with hydrogen, and was then heated to 200° C. whilestirring to perform hydrogenation. Four hours later, the heating wasstopped. The autoclave was cooled to 30° C. or less and was thendeaerated. Nitrogen purging was performed five times under a pressurizedatmosphere. The autoclave was opened and the reaction mixture wasfiltered to separate the catalyst. Furthermore, the catalyst was washedwith methanol. After the catalyst was removed, the resultant reactionmixture was analyzed by HPLC. N-[2-(1,3-dimethylbutyl)thiophen-3-yl]benzoic acid amide represented by general formula (1A5), wherein thedouble bond at the alkenyl portion of the starting material ishydrogenated, was produced with a yield of 93.1 molar percent(selectivity 97.9%).

EXAMPLE 14

The reaction was repeated as in Example 13. However, in this reaction, acatalyst including 80% of the recovered catalyst (0.65 g, i.e., 0.4 gdry weight of the catalyst), which was prepared by filtering in Example10, and 0.1 g dry weight of the new catalyst (1% of the compound) wasused. The atmosphere in the autoclave was purged with nitrogen.Subsequently, the autoclave was pressurized to 3 MPa with hydrogen, andwas heated to 200° C. while stirring to perform hydrogenation for 6hours. The subsequent process was performed as in Example 1 to determinethe yield. The compound represented by general formula (1A5) wasproduced with a yield of 94.0 molar percent (selectivity 98.9%).

EXAMPLE 15

The reaction was repeated as in Example 13. In this reaction, a catalystincluding 80% of the recovered catalyst (0.58 g, i.e., 0.4 g dry weightof the catalyst), which was prepared by filtering in Example 11, and 0.1g dry weight of the new catalyst (1% of the compound) was used. Theatmosphere in the autoclave was purged with nitrogen. Subsequently, theautoclave was pressurized to 3 MPa with hydrogen, and was heated to 200°C. while stirring to perform hydrogenation for 6 hours. The subsequentprocess was performed as in Example 1 to determine the yield. Thecompound represented by general formula (1A5) was produced with a yieldof 93.4 molar percent (selectivity 98.4%).

COMPARATIVE EXAMPLE 1

The reaction was performed as in Example 1. In this reaction, 0.5 g dryweight (5% of the compound) of palladium-carbon (E106 NN/W availablefrom Degussa) was used as the catalyst. However, methanol was used asthe solvent, and the reaction was performed at 30° C. for 7 hours. Thesubsequent process was performed as in Example 1 to determine the yield.The compound represented by general formula (1A5) was produced with ayield of 98.7 molar percent (selectivity 99.2%). Subsequently, all thecatalyst recovered from the above reaction system, and in addition, 0.1g dry weight of the new catalyst (1% of the compound) were charged. Thereaction was then performed at 30° C. for 9 hours. However, hydrogen wasbarely absorbed from 7 hours onward and the reaction was completed. Thesubsequent process was performed as in Example 1 to determine the yield.The yield of the compound represented by general formula (1A5) was notmore than 84.3 molar percent (selectivity 98.8%).

COMPARATIVE EXAMPLE 2

The reaction was performed as in Example 1. In this reaction, 0.5 g dryweight (5% of the compound) of palladium-carbon (E106 NN/W availablefrom Degussa) was used as the catalyst. However, methanol was used asthe solvent, and the reaction was performed at 100° C. for 1 hour. Thesubsequent process was performed as in Example 1 to determine the yield.The compound represented by general formula (1A5) was produced with ayield of 88.1 molar percent (selectivity 98.9%). Subsequently, thereaction was performed at 100° C. in the same way using all the catalystrecovered from the above reaction system. After the reaction had beenperformed for 1 hour, it had already reached a steady state. Thesubsequent process was performed as in Example 1 to determine the yield.The yield of the compound represented by general formula (1A5) was notmore than 12.7 molar percent (selectivity 99.9%).

COMPARATIVE EXAMPLE 3

The reaction was performed as in Example 1. However, in this reaction,1.0 g dry weight (10% of the compound) of palladium-carbon (S-Typeavailable from N.E. Chemcat Corporation) was used as the catalyst, andmethanol was used as the solvent. The reaction was performed at 100° C.for 1 hour. The subsequent process was performed as in Example 1 todetermine the yield. The compound represented by general formula (1A5)was produced with a yield of 99.1 molar percent (selectivity 99.3%).Subsequently, the reaction was performed in the same way at 100° C. for1 hour using all the catalyst recovered from the above reaction system,and the yield was determined. The compound represented by generalformula (1A5) was produced with a yield of 91.9 molar percent(selectivity 98.1%). Furthermore, the reaction in the second catalystrecycle was performed at 100° C. for 1 hour using all the catalystrecovered from the above reaction system, and the yield was determined.The compound represented by general formula (1A5) was produced with ayield of 46.8 molar percent (selectivity 97.7%).

Furthermore, the reaction in the third catalyst recycle was performed at100° C. for 1 hour using all the catalyst recovered from the abovereaction system. After the reaction had been performed for 1 hour, theabsorption of hydrogen had already stopped. The reaction was stopped,and the subsequent process was then performed to determine the yield.The yield of the compound represented by general formula (1A5) was notmore than 32.1 molar percent (selectivity 98.8%).

COMPARATIVE EXAMPLE 4

The reaction was performed as in Example 1. However, in this reaction,1.0 g dry weight (10% of the compound) of Raney-Ni (R-239 available fromNikko Rica Corporation) was used as the catalyst, and a xylene was usedas the solvent. The autoclave was sealed and nitrogen-purging wasrepeated five times. The pressure in the autoclave was then returned tonormal pressure. The autoclave was pressurized to 2.0 MPa with hydrogen,and was then heated to 160° C. while stirring to perform hydrogenationfor 12 hours. After the catalyst was removed, the resultant reactionmixture was analyzed by HPLC. The yield of the compound represented bygeneral formula (1A5) was not more than 61.0 molar percent (selectivity79.0%).

COMPARATIVE EXAMPLE 5

The reaction was performed as in Example 1. However, in this reaction,2.0 g dry weight (20% of the compound) of a copper catalyst (VF300-1available from Nikko Rica Corporation) was used, and octanol was used asthe solvent. The autoclave was sealed and nitrogen purging was repeatedfive times. The pressure in the autoclave was then returned to normalpressure. The autoclave was pressurized to 2.0 MPa with hydrogen, andwas then heated to 200° C. while stirring to perform hydrogenation for18 hours. After the catalyst was removed, the resultant reaction mixturewas analyzed by HPLC. The yield of the compound represented by generalformula (1A5) was not more than 76.3 molar percent (selectivity 84.9%).

REFERENCE EXAMPLE 1

It was assumed that the catalyst was inactivated because the compoundbefore hydrogenation or the reaction product was adhered to thecatalyst. Therefore, the sulfur (S) content in the catalyst wasmeasured. The sulfur content in the catalyst recovered in Example 1,which was used once in the reaction performed at 200° C., was 1.2%. Thesulfur content in the catalyst recovered in Example 3, which was usedthree times, was 1.6%.

REFERENCE EXAMPLE 2

In Comparative Example 3, the sulfur content in the catalyst used oncein the reaction performed at 100° C. and then recovered was 1.6%. Inaddition, the sulfur content in the catalyst used three times and thenrecovered was 3.1%. This result showed that the sulfur content after thereaction performed at 100° C. was significantly increased, compared withthat after the reaction performed at 200° C. (Reference Example 1).

INDUSTRIAL APPLICABILITY

According to the present invention, in the industrial scale productionof a compound such as a 2-alkyl-3-aminothiophene derivative representedby general formula (2) by reducing a sulfur-containing compound, forexample, represented by general formula (1), by hydrogenation in thepresence of a noble metal catalyst, the noble metal catalyst can berecycled to economical advantage. Consequently, the present inventionalso provides higher economical efficiency in the production of thecompound represented by general formula (2).

According to the production method of the present invention, thereduction by hydrogenation performed at a relatively high temperaturesuppresses the inactivation of the noble metal catalyst. Consequently,the method of the present invention allows the noble metal catalyst tobe recovered for reuse. The present invention provides an industrialscale method for producing the compound, for example, represented bygeneral formula (2), with economical efficiency.

1. A method for reducing a sulfur-containing compound by hydrogenation,the method comprising the steps of: hydrogenating the sulfur-containingcompound using a noble metal catalyst at a reaction temperature of 150°C. to 300° C.; recovering the used noble metal catalyst; and reusing thenoble metal catalyst.
 2. The method according to claim 1, wherein thenoble metal catalyst comprises palladium.
 3. The method according toclaim 1, wherein an alcohol of 1 to 8 carbon atoms is used as a reactionsolvent in the step of hydrogenating the sulfur-containing compound. 4.The method according to claim 3, wherein the sulfur-containing compoundis a thiophene compound.
 5. The method according to claim 4, wherein thethiophene compound is a thiophene amide.
 6. The method according toclaim 5, wherein the thiophene amide is represented by general formula(1):

(wherein R represents a hydrogen atom, a substituted or unsubstitutedalkyl group, a substituted or unsubstituted alkoxy group, a substitutedor unsubstituted aromatic hydrocarbon ring, a substituted orunsubstituted nonaromatic hydrocarbon ring, a substituted orunsubstituted aromatic heterocycle, or a substituted or unsubstitutednonaromatic heterocycle; R1, R2, R3, and R4 independently represent ahydrogen atom, or a linear or branched alkyl group of 1 to 12 carbonatoms; and R1 and R2, R3 and R4, R1 and R3, R1 and R4, R2 and R3, or R2and R4 may be bonded together to form a cycloalkyl group), and analkenyl group of the compound represented by general formula (1) isreduced by hydrogenation to produce a 2-alkyl-3-aminothiophenederivative represented by general formula (2):

(wherein R, R1, R2, R3,and R4 are as defined above).
 7. The methodaccording to claim 6, wherein R in the compounds represented by generalformula (1) and general formula (2) is a hydrogen atom, a substituted orunsubstituted alkyl group, a substituted or unsubstituted alkoxy group,or a substituted or unsubstituted phenyl group.
 8. The method accordingto claim 6, wherein R in the compounds represented by general formula(1) and general formula (2) is a group represented by general formulae(A1) to (A12):

(wherein R5 represents a trifluoromethyl group, a difluoromethyl group,a methyl group, an ethyl group, a hydrogen atom, or a halogen atom; R6represents a hydrogen atom, a methyl group, a trifluoromethyl group, ahalogen atom, a methoxy group, or an amino group; R7 represents ahydrogen atom, a halogen atom, a methyl group, or a methoxy group; R8represents a hydrogen atom, a methyl group, an ethyl group, or a halogenatom; and n represents an integer of 0 to 2; however, in generalformulae (A9), (A10), and (A11), R5 does not represent a halogen atom).9. The method according to claim 8, wherein R in the compoundsrepresented by general formula (1) and general formula (2) isrepresented by general formula (A1) in which R5 is a trifluoromethylgroup and R7 is a hydrogen atom.
 10. The method according to claim 6,wherein each of R1, R2, and R3 in the compound represented by generalformula (2) is a hydrogen atom and R4 in the compound represented bygeneral formula (2) is an isopropyl group.
 11. The method according toclaim 2, wherein the sulfur-containing compound is a thiophene compound.12. The method according to claim 11, wherein the thiophene compound isa thiophene amide.
 13. The method according to claim 12, wherein thethiophene amide is represented by general formula (1):

(wherein R represents a hydrogen atom, a substituted or unsubstitutedalkyl group, a substituted or unsubstituted alkoxy group, a substitutedor unsubstituted aromatic hydrocarbon ring, a substituted orunsubstituted nonaromatic hydrocarbon ring, a substituted orunsubstituted aromatic heterocycle, or a substituted or unsubstitutednonaromatic heterocycle; R1, R2, R3, and R4 independently represent ahydrogen atom, or a linear or branched alkyl group of 1 to 12 carbonatoms; and R1 and R2, R3 and R4, R1 and R3, R1 and R4, R2 and R3, or R2and R4 may be bonded together to form a cycloalkyl group), and analkenyl group of the compound represented by general formula (1) isreduced by hydrogenation to produce a 2-alkyl-3-aminothiophenederivative represented by general formula (2):

(wherein R, R1, R2, R3, and R4 are as defined above).
 14. The methodaccording to claim 13, wherein R in the compounds represented by generalformula (1) and general formula (2) is a hydrogen atom, a substituted orunsubstituted alkyl group, a substituted or unsubstituted alkoxy group,or a substituted or unsubstituted phenyl group.
 15. The method accordingto claim 13, wherein R in the compounds represented by general formula(1) and general formula (2) is a group represented by general formulae(A1) to (A12):

(wherein R5 represents a trifluoromethyl group, a difluoromethyl group,a methyl group, an ethyl group, a hydrogen atom, or a halogen atom; R6represents a hydrogen atom, a methyl group, a trifluoromethyl group, ahalogen atom, a methoxy group, or an amino group; R7 represents ahydrogen atom, a halogen atom, a methyl group, or a methoxy group; R8represents a hydrogen atom, a methyl group, an ethyl group, or a halogenatom; and n represents an integer of 0 to 2; however, in generalformulae (A9), (A10), and (A11), R5 does not represent a halogen atom).16. The method according to claim 15, wherein R in the compoundsrepresented by general formula (1) and general formula (2) isrepresented by general formula (A1) in which R5 is a trifluoromethylgroup and R7 is a hydrogen atom.
 17. The method according to claim 13,wherein each of R1, R2, and R3 in the compound represented by generalformula (2) is a hydrogen atom and R4 in the compound represented bygeneral formula (2) is an isopropyl group.
 18. The method according toclaim 1, wherein the sulfur-containing compound is a thiophene compound.19. The method according to claim 18, wherein the thiophene compound isa thiophene amide.
 20. The method according to claim 19, wherein thethiophene amide is represented by general formula (1):

(wherein R represents a hydrogen atom, a substituted or unsubstitutedalkyl group, a substituted or unsubstituted alkoxy group, a substitutedor unsubstituted aromatic hydrocarbon ring, a substituted orunsubstituted nonaromatic hydrocarbon ring, a substituted orunsubstituted aromatic heterocycle, or a substituted or unsubstitutednonaromatic heterocycle; R1, R2, R3, and R4 independently represent ahydrogen atom, or a linear or branched alkyl group of 1 to 12 carbonatoms; and R1 and R2, R3 and R4, R1 and R3, R1 and R4, R2 and R3, or R2and R4 may be bonded together to form a cycloalkyl group), and analkenyl group of the compound represented by general formula (1) isreduced by hydrogenation to produce a 2-alkyl-3-aminothiophenederivative represented by general formula (2):

(wherein R, R1, R2, R3, and R4 are as defined above).
 21. The methodaccording to claim 20, wherein R in the compounds represented by generalformula (1) and general formula (2) is a hydrogen atom, a substituted orunsubstituted alkyl group, a substituted or unsubstituted alkoxy group,or a substituted or unsubstituted phenyl group.
 22. The method accordingto claim 20, wherein R in the compounds represented by general formula(1) and general formula (2) is a group represented by general formulae(A1) to (A12):

(wherein R5 represents a trifluoromethyl group, a difluoromethyl group,a methyl group, an ethyl group, a hydrogen atom, or a halogen atom; R6represents a hydrogen atom, a methyl group, a trifluoromethyl group, ahalogen atom, a methoxy group, or an amino group; R7 represents ahydrogen atom, a halogen atom, a methyl group, or a methoxy group; R8represents a hydrogen atom, a methyl group, an ethyl group, or a halogenatom; and n represents an integer of 0 to 2; however, in generalformulae (A9), (A10), and (A11), R5 does not represent a halogen atom).23. The method according to claim 22, wherein R in the compoundsrepresented by general formula (1) and general formula (2) isrepresented by general formula (A1) in which R5 is a trifluoromethylgroup and R7 is a hydrogen atom.
 24. The method according to claim 20,wherein each of R1, R2, and R3 in the compound represented by generalformula (2) is a hydrogen atom and R4 in the compound represented bygeneral formula (2) is an isopropyl group.